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Hypogonadotropic Hypogonadism and Cleft Lip and Palate Caused by A

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Hypogonadotropic Hypogonadism and Cleft Lip and Palate Caused by A 666 LETTER TO JMG J Med Genet: first published as 10.1136/jmg.2004.026989 on 1 August 2005. Downloaded from Hypogonadotropic hypogonadism and cleft lip and palate caused by a balanced translocation producing haploinsufficiency for FGFR1 HG Kim, S R Herrick, E Lemyre, S Kishikawa, J A Salisz, S Seminara, M E MacDonald, G A P Bruns, C C Morton, B J Quade, J F Gusella ............................................................................................................................... J Med Genet 2005;42:666–672. doi: 10.1136/jmg.2004.026989 e have established the Developmental Genome Anatomy Project (DGAP; //dgap.harvard.edu) to Key points Wtake advantage of the unique opportunity to locate genes of developmental importance provided by apparently N Kallmann’s syndrome (KS), characterised by hypogo- balanced chromosomal rearrangements associated with nadotropic hypogonadism and anosmia, can be phenotypic abnormalities. By positional cloning at or near caused by inactivating mutations of the X linked KAL1 the breakpoints, we aim to identify the crucial disease genes gene, but these mutations account for less than 15% of 1 whose functions have been disrupted by rearrangement. KS patients. The remaining cases, as well as cases of Kallmann’s syndrome (KS) is a developmental disorder hypogonadotropic hypogonadism without anosmia, characterised by anosmia resulting from agenesis of the are believed to be caused by mutations at two or olfactory lobes and hypogonadism secondary to deficiency of more autosomal loci, including a segment of 8p hypothalamic gonadotropin releasing hormone (GnRH). Its heterozygous for a microdeletion in one KS patient. prevalence has been estimated at 1/10 000 in males and 1/ 50 000 in females. In a minority of cases there are N Recently, mutation in FGFR1, the 8p gene encoding inactivating mutations of KAL1, an X linked gene encoding fibroblast growth factor receptor 1, has been shown to a putative adhesion molecule thought to mediate embryonic cause autosomal dominant KS. We report positional neuronal migration.23Constitutional autosomal chromosome cloning of the genomic breakpoints of the balanced translocations associated with KS have been reported, but the reciprocal translocation t(7;8)(p12.3;p11.2) from a disrupted genes have not been identified.4–6 male patient with hypogonadotropic hypogonadism We have studied a white male subject with a de novo and cleft lip and palate. The translocation disrupts balanced translocation between chromosomes 7, in band FGFR1 (MIM 136350) between exons 2 and 3 and p12.3, and 8, in band p11.2 (fig 1A), who was diagnosed on predicts a novel fusion gene product. http://jmg.bmj.com/ clinical examination to have hypogonadotropic hypogonad- N Although various FGFR1 translocations producing ism (infantile testes), azoospermia, and cleft lip and palate, fusion proteins have been reported as causes of without frank anosmia. As a KS patient with a microdeletion myeloproliferative disorders, this is the first case in involving the same 8p11.2 region had been reported, we which a constitutional FGFR1 translocation is asso- sought to identify the chromosome 8 gene disrupted in this ciated with a developmental disorder. reciprocal translocation as a likely candidate for the cause of autosomal KS as well as of isolated hypogonadotropic hypogonadism.7 While this breakpoint in FGFR1 was being on September 30, 2021 by guest. Protected copyright. characterised, Dode´ et al identified FGFR1 mutations in of anosmia. He was prescribed a regimen of testosterone several patients, establishing that disruption of FGFR1 can injections, which successfully induced secondary sexual cause autosomal dominant KS.8 characteristics. At the age of 31, he was seen by a different physician for azoospermia and infertility, and cytogenetic METHODS analysis was ordered for the possibility of Klinefelter’s This study was approved by the Institutional Review Board of syndrome. The analysis revealed an apparently balanced Partners Healthcare Inc, encompassing both the chromosomal translocation with the karyotype, Massachusetts General Hospital and the Brigham and 46,XY,t(7;8)(p12.3;p11.2). Informed consent for the genera- Women’s Hospital. tion of a lymphoblastoid cell line was obtained in accordance with institutional policies.9 Case report The subject is a white man who was aged 24 years at the time Fluorescent in situ hybridisation analysis of initial diagnosis. He had a history of cleft palate, corrected Breakpoint mapping on chromosome 8 was initiated using by surgery. He had no outstanding medical problems other clones placed on the cytogenetic map by fluorescent in situ than delayed sexual development and a feminine sounding hybridisation (FISH) analysis and on the sequence map by voice. He had his growth spurt at age 18–19 years, developed sequence tagged sites.10 Metaphase chromosomes from the sparse armpit hair at age 20, and penile hair at 16–17, but no patient cell line were prepared for analysis by GTG banding or penile or testicular enlargement. He displayed child-like FISH using standard protocols. Briefly, clones for FISH were facial hair, sparse axillary adult appearing hair, and prepubertal chest hair. Based on the presence of cleft palate Abbreviations: FGF, fibroblast growth factor; FISH, fluorescent in situ and hypogonadism, a tentative diagnosis of Kallmann’s hybridisation; KS, Kallmann’s syndrome; SSCP, single strand syndrome was reached, though the subject did not complain conformation polymorphism; UCSC, University of California Santa Cruz www.jmedgenet.com Letter to JMG 667 J Med Genet: first published as 10.1136/jmg.2004.026989 on 1 August 2005. Downloaded from Figure 1 Fluorescent in situ hybridisation (FISH) mapping of the chromosome 8 breakpoint. (A) Ideogram illustrating the balanced t(7;8)(p12.3;p11.2) in the patient. (B) FISH mapping with RP11-100B16, labelled with SpectrumOrange, resulted in hybridisation to the normal chromosome 8, and the der(8) and der(7) derivative chromosomes. The insets present the derivative chromosomes at higher magnification. selected using genome maps provided by the National Center 59GCAAGCTGTGCTGGAAGCA39;59CCAGCTTCACAGGTG for Biotechnology Information and the University of TTTTC39+59CCAGCATTTGAAGAGGGAGT39. California Santa Cruz (UCSC) Genomics Bioinformatics Group.10 11 Bacterial artificial chromosome (BAC) clones were Fusion transcript amplification obtained from CITB-D and RP11 libraries (Invitrogen, San Total RNA was isolated from patient and control lympho- Diego, California, and the Children’s Hospital of Oakland blastoid cell lines with the RNeasy Mini Kit (Qiagen, Research Institute) and directly labelled with Valencia, California, USA). Reverse transcription of total SpectrumOrange or Green-dUTP (Vysis) by nick translation. RNA (1 mg) was undertaken by using either random Hybridisations were carried out according to manufacturers’ hexanucleotide priming and Superscript II (Gibco BRL, protocols. Metaphase chromosomes were counterstained Gaithersburg, Maryland, USA) or the SMART–PCR cDNA with 4,6-diamino-2-phenylindole-dihydrochloride (DAPI), synthesis kit (Clontech, Palo Alto, California, USA) according and at least 10 metaphases were analysed using a Zeiss to the protocols provided. In each experiment, DNA Axioskop microscope. Images were captured with the contamination was excluded by the absence of a PCR product CytoVision system (Applied Imaging, San Jose´, California, in the sample without reverse transcriptase, amplified under USA). The karyotype, 46,XY,t(7;8)(p12.3;p11.2), was recon- the same conditions as the reverse transcribed RNA sample. firmed by GTG banding before breakpoint mapping by FISH. Nested PCR was carried out using Pfu polymerase (Gibco BRL) with the following primer sets, annealing at 56˚C for 30 http://jmg.bmj.com/ seconds with an extension for one minute 40 seconds: Mapping and cloning of breakpoints TENS1-FGFR1:59CTGAGAAAGCCCTCAGTGTCC39+59CAAG Southern blot analysis of patient lymphoblast genomic DNA ATCTGGACATAAGGCAGG39,59GGCAGAGCAGCTACTCC with probes D011-A, D011-B, and D011-C to search for ACA39+59GTCACTGTACACCTTACACATGAACTC39; FGFR1- altered restriction fragments was carried out using standard TENS1:59CCTCTTGCGGCCACAGGC39+59CCTTCAACATGGC protocols. For each lane, 10 mg of genomic DNA from the GATGG39,59GCAGCGCGCGGAG39+59CCTTGTACCAGAACTT patient and control were digested with an appropriate GGAAGTG39. restriction enzyme. Fragments were separated on a 1.0% on September 30, 2021 by guest. Protected copyright. agarose gel and transferred to Hybond-N membrane Mutation analysis (Amersham, Arlington Heights, Illinois, USA). Filters were Mutation analysis of the second allele of FGFR1 was done by ultraviolet cross linked, baked at 80˚C, and hybridised with single strand conformation polymorphism (SSCP). In all, 24 32 probes labelled with P-dCTP by random priming. genomic fragments including the entire coding region, UTR, Hybridisation of labelled fragments was done in the presence and intron–exon boundaries were amplified from 18 exons of of excess herring sperm competitor DNA, and hybridised FGFR1 by PCR with [32P]-dCTP. Primers were designed to membranes were washed at 60˚C with 0.15 M NaCl/0.015 M amplify genomic fragments with the size of 200 to 300 base sodium citrate/0.1 % sodium dodecyl sulphate (SDS) for 30 pairs (bp) (primer sequences and amplification conditions minutes. Autoradiography took place for 16 hours at –70˚C are available on request). PCR products were applied on non- using two intensifying
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